Method for short-term and long-term drug dosimetry

ABSTRACT

Methods for the treatment of interferon-response disorders by administration of an interferon alone or in combination with adjunctive therapy are described. The invention encompasses providing to a patient both a formulation of an interferon that is suitable for short-term administration and a formulation of an interferon associated with a sustained release delivery system that is suitable for long-term administration. A principal advantage of the method is that responsiveness to treatment can be ascertained with short-term dosimetric techniques using one formulation of an interferon, which permits the appropriate selection of a dose that is both effective and safe for long-term administration using the second formulation.

CROSS-REFERENCE

[0001] This application claims benefit under 35 U.S.C. §119(e) of U.S.provisional application 06/245,883 filed Nov. 3, 2000. The provisionalapplication is incorporated herein in its entirety.

FIELD OF THE INVENTION

[0002] This invention relates to a method and a kit for treatingdisorders, especially interferon-responsive disorders in warm-bloodedanimals and a method for individualizing doses of a drug, e.g. aninterferon, in treating such disorders. It further relates to a methodfor preparing a long-term dosage for treating such disorders.

BACKGROUND OF THE INVENTION

[0003] Introduction

[0004] Long-term delivery of drugs using a device that provides aconstant delivery of a drug over time has significant advantages overdelivery of a drug by regular injections or even oral delivery. Oneadvantage is that the patient may avoid “peak-related” adverse effects.Another advantage is that the patient may avoid “trough-related”ineffective therapy. Another advantage is avoiding frequent andsometimes painful injections for drugs that can't be administeredorally. However, one disadvantage of long-term, constant-rate deliveryof drugs is that there has not been an easy way to adjust doses for anindividual patient in a given population of patients having a disease.For example, in populations with hepatitis C, individual patients willrequire different dosage levels of drug for treatment depending on viralload, patient age and size, etc. The use of interferons is illustrative.

[0005] Interferons

[0006] The interferons are a group of endogenous proteins produced inresponse to a number of infectious, proliferative or immunologicaldisorders. Endogenous interferons have antiviral, immunomodulatory, orantiproliferative activities. The alpha and beta interferons are knownas type I interferons because these molecules appear to bind to a commonreceptor, the so-called α-β receptor. Exogenous interferons, such asrecombinant alpha (of various subtypes) or recombinant consensusinterferon, have been demonstrated to be useful in the treatment of, forexample, viral hepatitis C and certain cancers. A small percentage ofpatients who are treated with alpha or consensus interferon for periodsof several months may no longer manifest positive blood tests forhepatitis C viral ribonucleic acid (HCV-RNA). Such treatment may involveonly monotherapy with the interferon, or the interferon may be combinedwith another adjunctive therapeutic agent. Certain cancers also maystabilize or shrink in size with interferon monotherapy or withcombination treatments. Exogenous beta interferon (of various subtypes)has been shown to be useful as monotherapy in the treatment of multiplesclerosis. Exogenous gamma interferon has been shown to be useful asmonotherapy in the treatment of chronic granulomatous disease and morerecently has been suggested to be useful in the treatment of certainpulmonary disorders. Certain interferons have been chemically modifiedby the addition of polyethylene glycol or polyethylene oxide polymers(pegylated interferon) and may have enhanced antiviral activity in vivoas a result. Other forms of interferon-like peptides have been createdusing techniques to modify genes.

[0007] Adjunctive Therapeutic Agents

[0008] Ribavirin is a small organic molecule which, among otheractivities is known to inhibit inosine monophosphate dehydrogenase, hasantiviral and immunomodulatory activities. The addition of ribavirin toan alpha interferon, for example, may increase the long-term responserate in patients with hepatitis C. Other inhibitors of inosinemonophosphate dehydrogenase may also be useful as adjuncts to alphainterferon in certain clinical settings, as may other classes ofadjunctive therapy such as: interleukin-2, interleukin-2 analogs orderivatives, histamine, histamine analogs or derivatives; a monoclonalantibody or antibodies; a polyclonal antibody or antibodies; or anycombination thereof.

[0009] Limitations of Interferon Treatment

[0010] These current antiviral therapeutics are, however, not withoutlimitations. For example, the long-term success rate in the treatment ofhepatitis C is estimated to be for: alpha interferon alone (≈10-15%);consensus interferon alone (≈10-15%); pegylated alpha interferon alone(≈20-25%); alpha interferon combined with ribavirin (≈30-40%); and alphainterferon plus a histamine-related compound (≈30-40%). There isevidence that treatment with the combination of alpha interferon andribavirin or histamine analogs may induce responses in patients whoappeared not to be fully responsive to alpha interferon alone. Consensusinterferon in high doses has been reported to induce responses inpatients who failed to achieve sustained results on lower doses of alphainterferon.

[0011] Resistance and Side Effects

[0012] In a large percentage of patients, however, there is nosignificant antiviral activity by either alpha or consensus interferon,whether or not combined with another agent. The patients are said toexhibit primary viral resistance. In addition, a significant fraction ofpatients whose disease does respond initially do not have a sustainedresponse after drug therapy has ceased. The patients are said to exhibitsecondary viral resistance. Among those patients who fail to respond toalpha interferon, the majority also fail to respond to subsequenttreatment with consensus interferon. The reasons for primary orsecondary resistance are not completely understood but may involvesignificant variations in blood levels of the interferon, thedevelopment of antibodies directed against the interferon, the geneticfeatures of the virus and/or the patient, or changes in the virus and/orthe patient.

[0013] Furthermore, not all patients can tolerate therapy with aninterferon, whether alone or in combination with an adjunctivetherapeutic agent, because of adverse side effects. Some side effectsmay be worsened by the addition of ribavirin, interleukin-2, or otheradjunctive therapies now in use or under development. Moreover, certainpatients who have been characterized initially as “resistant” to alphainterferon appear to respond to alpha interferon when a second orsubsequent course of therapy is given, suggesting that the patient mayhave been inadequately treated during the earlier course of therapy orotherwise not truly resistant. Patients failing alpha interferon who aresubsequently “responsive” to consensus interferon may be in a similarcategory, i.e., inadequately treated during the initial course oftherapy. Inadequate treatment can easily occur if the initial durationof treatment is too brief or the dose for a particular patient is toolow, leading to misleading or false conclusions regarding viralresistance.

[0014] Problems with Short-term Administration

[0015] In addition, whether used as monotherapies or as part ofcombination therapies, currently available injectable interferons areinconvenient for patients to administer over a long period of time. Theprincipal reason is the required frequency of injections, from one ormore times per day to once per week. The dose of a drug in a formulationintended for short-term usage and frequent administration can be rapidlychanged. Nonetheless, there is still a significant risk of peaks in drugconcentration in blood or tissues (occurring immediately after or earlyin the dosing cycle) and troughs (occurring just before the next dose isto be administered).

[0016] This phenomenon can be particularly troublesome with aninterferon formulated for short-term usage with frequent administrationsrequired. With peak levels, there may be an increase the risk oftroublesome side effects and with prolonged trough levels, there may beperiods of time when there is little or no interferon activity ispresent in the blood or tissues.

[0017] In summary, any formulation of an interferon intended forshort-term usage is usually highly adjustable with respect to the doseof the drug but also highly inconvenient for long-term administration.

[0018] Problems with Long-term Administration

[0019] A sustained release preparation of an interferon with a depotform capable of delivering a biologically active drug at a stable ratefor many months, or a year or even longer, would have many potentialadvantages. There are many potential forms of a sustained releasepreparation including but not limited to: an implantable, non-erodibledevice with a reservoir capable of holding the drug isolated from thetissues and then releasing the drug at a controlled rate systemicallyinto the body, or locally into a single organ or site; an implantableerodible device or matrix with drug in or on the matrix capable ofsystemic or local delivery; a gel or other suspension containing thedrug capable of controlled-rate systemic or local delivery; an externalpump for IV delivery; a patch or other controlled-rate transdermaldelivery system. The drug may be delivered as the unmodified molecule orcoupled covalently or non-covalently to carriers, polymers, nonpolymersor other molecules, from which the original molecule is released in itsoriginal or still modified form. Those skilled in the arts willrecognize that there are many other forms of chronic controlled-ratedelivery systems that could be employed.

[0020] One of the potential advantages of any sustained release systemwould be the avoidance of frequent and painful injections, therebyminimizing the possibility that doses would be missed which couldpotentially lead to ineffective therapy. Another advantage would be thepotential for maintaining stable or even fixed rate of delivery of adrug systemically or locally, thereby minimizing the chances for“peak-related” adverse effects and/or “trough-related” ineffectivetherapy.

[0021] There are also potentially significant disadvantages with anylong-term depot. Any such formulation would necessarily involve,relative to a short-term daily or weekly dose, the administration of arelatively large and potentially very costly amount of drug. If there isoccurrence in the patient of a severe side effect requiring an immediatereduction in the dose, such a reduction would be practically impossibleor very difficult with any long-term sustained release preparation thathad been implanted or injected. For a mechanical device, an erodiblematrix, or a gel or other suspension it may be necessary to perform aninvasive procedure to attempt to remove all or part of the administereddrug. For all except the use of a mechanical device or transdermalpatch, in fact, which hold the drug intact within a reservoir physicallyisolated from the body, it might be impossible to remove all of thedrug. Accordingly, while long term administration of an interferonoffers many advantages to a patient, any error in selecting thelong-term dose level or long-term drug delivery rate could have veryadverse and costly consequences.

[0022] Moreover, for patients with certain diseases such as viralhepatitis C, it may be desirable to individualize the dose as much aspossible. Historically, patients have been treated with a fixed amountof interferon per week and such amounts have been maintained at thefixed level for many weeks or months in the absence of supervening sideeffects that mandated a reduction in dosage. Short-term delivery of aninterferon offers the potential advantage of permitting doses to beadjusted readily, while long term administration of a fixed rate of drugdelivered from, for example, a reservoir permits no adjustment at all.

[0023] In summary, a formulation of a drug, such as an interferon, usedwith a long term delivery system or device is highly convenient forensuring stable delivery of drug, but is relatively or absolutelyinflexible with regard to adjustment of the drug and potentiallyexpensive or requiring invasive procedures to reduce the amount oreliminate the drug from the body altogether.

[0024] Advantages of the Present Invention

[0025] I have now invented an approach that addresses the problems inthe prior art in the long-term use of a drug, e.g. an interferon, forthe treatment of disease of warm-blooded animals that require long termadministration to treat the disease or condition, e.g. one that isinterferon-responsive.

[0026] My invention maximizes the probability of delivering an effectivedose of a drug, such as an interferon, to a warm-blooded animal with,e.g. an interferon-responsive disease or condition and further maximizesthe chances of delivering a safe dose of the drug, such that the dose isminimally toxic and therefore tolerated by the recipient.

[0027] My invention further facilitates the selection of a safe,tolerated and effective dosage of a drug, e.g. an interferon, to bedelivered to a warm-blooded animal by a long-term delivery system andfacilitates dose-individualization of the drug for an individual patientin the setting of long-term administration using a long-term deliverysystem.

[0028] My invention also minimizes or eliminates the need to alter therate or change the dose-rate of the drug once long-term dosing hascommenced with a long-term delivery system.

[0029] Further, in the event that dose- or rate-adjustment is required,my invention aids in minimizing the negative impact on therapy and costof any such adjustment in dose or rate after the commencement of dosingwith a long-term delivery system.

[0030] My invention also provides for combination therapy using, forexample, interferon and one or more non-interferon adjunctivetherapeutic agents or even a second, structurally distinct interferon.

SUMMARY OF THE INVENTION

[0031] One aspect of the invention is a method for the treatment of adisorder, e.g. an interferon-responsive disorder, in a warm-bloodedanimal. The method comprises administering at least one drug, e.g. aninterferon, formulated for short-term use, adjusting the dosage of theshort-term formulation to increase and preferably maximize therapeuticresponse while simultaneously decreasing and preferably minimizingadverse side effects, and subsequently selecting a dosage to beadministered with a long-term delivery system and long-term formulationsuitable for use in the long-term delivery system. Thereafter thelong-term dosage is delivered with the long-term delivery system and, ifnecessary, the dosage is subsequently adjusted with the long-termformulation and long-term delivery system to further maximizetherapeutic response while simultaneously minimizing adverse sideeffects.

[0032] Another aspect of the invention is a method for individualizing adose of a drug, such as an interferon, in the treatment of a disorder,e.g. an interferon-responsive disorder, in a warm-blooded animal. Themethod allows a physician to establish a dosage for treating a specificpatient for his or her individual needs over the length of treatment.The method comprises administering at least one drug, e.g. aninterferon, formulated for short-term use, adjusting the dosage with theshort-term formulation to increase and preferably maximize therapeuticresponse while simultaneously decreasing and preferably minimizingadverse side effects in a plurality of patients and determining the mostcommonly identified optimal dosage in a sufficiently large population ofsuch patients to define this dosage as a unit dose. Subsequently, usinga long-term formulation and a long-term delivery system, at least oneunit-dose, optionally with one or more fractional unit doses, isadministered such that, in aggregate, the optimal dosage identifiedduring dosing with the short-term formulation can be approximated withthe unit-dose/fractional unit-dose combination using the long-termformulation and long-term delivery system. Thereafter, a dosage isselected and administered with a long-term formulation in the long-termdelivery system. The long-term dosage is administered via the long-termdelivery system and the dosage of the long-term formulation vialong-term delivery system is optionally adjusted to further maximizetherapeutic response while simultaneously minimizing adverse sideeffects.

[0033] Another aspect of the invention is a method of manufacturing along-term delivery system for delivering a drug over time. The methodcomprises preparing a long-term delivery device designed for delivery ofa drug at a specified constant rate over time, the rate being determinedto be a standard dosage rate to treat a disease state in the patienttreatable over time by the drug, and preparing a second long-termdelivery device designed for delivery of the same drug at a specifiedconstant rate over time, which rate is a fraction of the standard dosagerate of the first device. Each device is suitable for presentation to apatient in need thereof alone or in combination, depending on the dosagerate or fractional dosage rate determined to be appropriate for thepatient. The patient may then have a device delivering a standard dosagerate or some fraction lesser or greater than the standard dosage rate,depending on the characteristics of the patient, e.g. age, gender,weight, physical condition, etc.

[0034] Still another aspect of this invention is a kit useful fordelivery of a constant amount of a drug thereof over time, wherein theamount of drug delivered to an individual patient within a populationcan be adjusted to the patient's individual needs for treatment. The kitcomprises (a) at least one long-term delivery device designed fordelivery of a drug at a constant rate over time, the rate beingdetermined to be a unit rate as a standard dosage to treat a diseasestate in a patient in the population over time, and (b) at least onelong-term delivery device designed for delivery of the same drug at arelatively constant rate over time, which rate is a fraction of thestandard dosage rate, wherein each device in the kit is suitable forpresentation to a patient in need thereof alone or in combination withan identical device or the device having a different delivery ratedepending on the dosage rate determined to be appropriate for thepatient. Alternatively, the kit comprises at least two long-termdelivery devices designed for delivery of the same drug at the same ordifferent constant rates over time, for which each rate is a fraction ofthe standard dosage rate, wherein each device in the kit is suitable forpresentation to a patient in need thereof along or in combination withan identical device or the other device, depending on the dosage ratedetermined to be appropriate for the patient.

[0035] The invention is particularly valuable for the administration ofomega interferon, but also encompasses the use of other drugs, e.g.interferons (or mixture thereof) that bind to and activate interferonreceptors in warm-blooded animals with an interferon-responsive diseaseor condition. The invention also encompasses combination therapies ofdrugs, such as an interferon, or mixture thereof, and one or morenon-interferons or even a second, structurally distinct interferon. Theinvention is particularly valuable for the administration of omegainterferon to treat hepatitis C.

[0036] The invention is also useful for the administration of any highlypotent molecule, e.g., cytokines, hormones, or congener or analogthereof, for which there are significant side effects that can belessened and/or benefits that can be increased by the appropriateselection of short and long-term doses. The invention is particularlyvaluable for the administration of: growth hormone to treat growthdefects and injuries to tissues; sex hormones such as luteinizinghormone or related releasing factors such as luteinizing hormonereleasing hormone to treat endocrine disorders or cancer.

[0037] The invention is not limited by the number of differentformulations. If a relatively smaller amount of, for example, interferon(whose duration in the body is measured in hours to days) is deliveredby a formulation that can be used to assess the safety, tolerability,and efficacy of a larger amount of the same or different interferondelivered in the same formulation (but whose duration in the body ismeasured in weeks or months because of the larger amount provided), thecurrent invention also encompasses this differential use of a singleformulation to effect both short-term and long-term therapy. The largeramount will differ from the smaller amount by a preferred factor of atleast four, more preferred at least twelve, and most preferredtwenty-four or higher.

[0038] The therapeutic method of the present invention is amenable tointermittent or repeated use for the treatment of acute, chronic,remitting or relapsing diseases or conditions.

[0039] The therapeutic method of the present invention can be utilizedif there is little or no delay in transitioning from short- to long-termtherapy (minutes to days) or if there is a delay in transitioning fromshort- to long-term therapy (weeks to months). For example, short-termdosing with an interferon such as omega interferon could occur at asingle dose level during days 1-14 of therapy and, based on theinformation obtained regarding signs, symptoms, and laboratory valuesduring these first 14 days, appropriate long-term therapy could begin onday 15. Alternatively, and again by way of example, short-term dosingcould occur during days 1-14, followed by a second but differentshort-term dosing from days 15-28, and long-term therapy could begin onday 29. In another example, information regarding responsiveness andtolerability to a short-term formulation of an alpha or gamma interferoncould be obtained during 1-12 months of prior treatment. During this1-12 month period, the dose of alpha or gamma could remain the same orbe altered according to patient response and adverse side effects.Thereafter, a period of indeterminate length without treatment couldoccur. Treatment could be halted for any of several reasons includingincomplete therapeutic response or unacceptable adverse events. Forexample, then, a no-treatment period could also be of 1-12 monthsduration. Thereafter, but still based on the information obtained duringthe 1-12 months of prior active treatment, therapy with a long-termdosing formulation of the same or a different interferon could begin.

[0040] Other aspects of the invention may be apparent to one of skill inthe art upon further reading the following specification.

BRIEF DESCRIPTION OF THE DRAWINGS

[0041]FIG. 1 is a graph showing the change in HCV RNA levels versus timein individual human subjects with chronic hepatitis C infectionresistant to 3-12 months of treatment with alpha interferon with orwithout ribavirin.

[0042]FIG. 2 is a graph showing that increasing doses of omegainterferon produce progressively larger viral clearance rates (responserate) in patients with chronic hepatitis C infection who were previouslyuntreated with an interferon.

[0043]FIG. 3 is a graph showing the pharmacokinetics of omega interferon(plasma concentration vs. time) after a single dose of omega interferonin humans. The median half-life of absorption is 3.1 hours; the medianhalf-life of elimination is 11.4 hours.

[0044]FIG. 4 is a graph showing the calculated pharmacokinetic profileof omega interferon with once daily (q 24 hour) and 4 times daily (q 6hour) dosing cycles, with the same total daily dose of 15 μg.

[0045]FIG. 5 is a depiction of one sequence of events in adjusting thedose using the short-term formulation 1, selecting the dose level foruse with long-term formulation 2 and its associated long term deliverysystem. The period of transition can be of any duration.

DETAILED DESCRIPTION OF THE INVENTION

[0046] Method of Treatment

[0047] One aspect of the invention is a method for the treatment of adisorder, e.g. an interferon-responsive disorder, in a warm-bloodedanimal. The method comprises the following steps:

[0048] administering at least one drug, e.g. an interferon, formulatedfor short-term use, adjusting the dosage of the short-term formulationto improve the therapeutic index in a patient with a disease orcondition responsive to the drug, thereby achieving a desirabletherapeutic response with no, few or clinically acceptable adverse sideeffects;

[0049] based on the clinical information gained during administration ofthe short-term formulation, selecting the dosage to be administeredinitially as a long-term formulation and selecting the time at which thetransition from short-term formulation to long-term formulation occurs,and thereby retaining or further enhancing therapeutic index

[0050] based on the clinical information gained during administration ofthe short-term formulation, selecting the time at which the transitionfrom short-term formulation to long-term formulation occurs, and therebyretaining or further enhancing therapeutic index

[0051] thereafter adjusting the dosage of the long-term formulation,preferably but not necessarily upwards, if and as required.

[0052] The method of the current invention has several benefits.Consider, for example, the clinical setting in which a long-termdelivery system is used with a drug that has the potential for serioustoxicity, has the potential for different or progressive toxicities overtime, has a narrow or even no therapeutic window (i.e., the effectivedose-range is similar to or overlaps the toxic dose-range), is veryexpensive, or a combination of these factors. Currently, interferons arecostly, have a narrow or no therapeutic window and can cause differenttoxicities over time. Therefore, an interferon represents one such drug.For such drugs, the selection of dose or changes thereof should be madewith great care.

[0053] The treatment of hepatitis with an interferon is an example ofone clinical setting in which an interferon-responsive disorder must betreated typically for several months to a year or longer. If ahealth-care provider begins treatment with a long-term delivery system,e.g., where weeks or months of treatment are possible with a singleadministration, then the selection of the long-term dose is of criticalimportance.

[0054] It is worth noting that the administration of an interferon forlong-term delivery will generally involve the delivery of drug at moreor less a fixed rate throughout the course of therapy if system start-upor shut-down effects, if any, are ignored. Long-term delivery systemssuch as gels or polymers, once injected or implanted, typically erode ordissolve at rates that cannot be changed without surgical intervention.Implantable pumps that cannot be externally programmed or adjusted tochange the rate of delivery would require replacement or removal toeffect a dose change.

[0055] Consider the example where a long-term dose is selected and iseffective but causes severe or serious side effects shortly after theinitiation of treatment, e.g., after only a small percentage of thetotal dose is delivered. Then, in order to protect the patient it may benecessary to remove part or all of the drug-delivery system in order toreduce the dose or dose-rate. Alternatively, consider the example wherea long-term dose is selected and is effective and initially welltolerated but a serious or severe adverse effect appears later, but at atime when a clinically and economically meaningful percentage of drugstill remains in the system. Then, in order to protect the patient itmay still be necessary to remove part or all of the drug-delivery systemin order to reduce the dose or dose-rate. Such removal may or will:

[0056] involve procedural risk, expense, and time for the patient

[0057] waste some or all of the (expensive) drug that had beenadministered

[0058] reduce the chances for effective therapy

[0059] may induce the patient or health-are provider to abandon apotentially convenient, safe and effective therapy.

[0060] Therefore, it is very desirable to avoid the early or otherwiserisky or wasteful removal of the long-term delivery system. The methodof the current invention makes possible the achievement of this goal.

[0061] The benefits of the method of the current invention may befurther exemplified. In the treatment of a disease or medical conditionit is generally desirable to effect a therapeutic response as rapidly asis safely possible. This means that the onset of drug action isappropriately rapid. However, when a sufficiently severe adverse sideeffect occurs, the typical response is to stop administration of theoffending drug and to wait for the offset of drug action. Clearly, it isdesirable to have a rapid offset if a severe side effect occurs.Preferably the offset will be measured in minutes to a few hours.Examples of drugs with relatively rapid onset, possible severe sideeffect, but relatively rapid offset include the following drugsadministered by injection or infusion in a suitable short-termformulation include heparin that induces bleeding or penicillin thatinduces an allergic response.

[0062] Four examples of drugs administered by injection or infusion thathave less rapid offset (many hours to days or weeks) but are associatedwith serious side effects include cyclophosphamide and bone marrowcellular depletion, cyclosporine and acute infection, interferons andgranulocytopenia, or interferons and depression or suicidal ideation.Any of these side effects may be sufficiently severe to put a patient'slife in jeopardy or to result in the death of a patient. In the presenceof such adverse side effects it may be necessary in these four clinicalsettings, respectively, to stop the offending drug and to administergranulocyte colony stimulating factor to increase cell count, toadminister antibiotics to combat infection, wait until granulocyte countreturns to normal before resuming treatment at a lower dose, or tohospitalize the patient and give antidepressants, electric shocktreatment or even maintain constant physical restraint.

[0063] In the case of an interferon dose that could deliver drug forweeks or months, the appearance of granulocytopenia can be rapid,occurring within a matter of a few days to weeks. Halting therapy orimmediately reducing the dosage is necessary in order to reduce the riskof serious infection. An injectable form of interferon typicallypersists in the body for several hours or, in the case of pegylatedinterferons, for a week or more. In either case, the use of a short-terminjectable can be modified or halted immediately after granulocytopeniais detected. Recovery is typically rapid, within days, and therapy canbe resumed or continued at a lower dose. However, if a multimonth formof the interferon were present instead in the form of, for example, aninjected gel or polymer or implanted pump, then granulocytopenia wouldpersist or worsen during continued presence of the drug-until and unlessthe gel, polymer, or pump is surgically excised or extracted. For thereasons stated above, a sudden and unplanned removal of a long-termdelivery system is very undesirable.

[0064] With the method of the present invention, the short-termformulation is administered and adjusted until the desired therapeuticeffect is achieved and, if adverse side effects occur acutely during afew days or weeks after beginning therapy, the dosage is lowered toreduce these effects. Then, and only then, the long-term dose isselected and the long-term delivery system injected or implanted,thereby retaining the benefits of the prior short-term dose selection.

[0065] In the case of an interferon dose that could deliver drug forweeks or months, the appearance of, for example, suicidal ideation afterseveral weeks or months of interferon therapy would constitute a medicalemergency. The method of the current invention can reduce this risk. Byapplying the method described herein, treatment with the short-termdosing form could be continued for many weeks or months in selectedpatients and after the risk of depression or suicidal ideation wasjudged to have passed or to be low, then an appropriately selectedlong-term dose can be administered.

[0066] Those skilled in the art will recognize other benefits of thecurrent invention not described in the examples contained herein.

[0067] While the various aspects of this invention relate to thelong-term delivery of drugs generally, the details of the invention areexplained using interferons, particularly omega interferon, as the drugsof choice. The term “interferon” (or “interferons”) is meant to beinterpreted in its broadest sense, i.e. glycoproteins that are potentcytokines, i.e. hormone-like low molecular weight proteins that regulatethe intensity and duration of immune responses and are involved incell-to-cell communications. The interferons possess complexanti-infective (e.g. antiviral), immunomodulating, and antiproliferativeactivity. Thus, the interferons are used for treating disorders of viralorigins, disorders of the immune systems, and disorders generallyreferred to as cancers, i.e. malignant neoplasms. These disorders arereferred to as “interferon-responsive disorders.” The types ofinterferon (“IFN”) include both naturally-occurring and recombinant IFN,e.g. alpha(alfa)-IFN, beta-IFN, gamma-IFN, tau-IFN, consensus IFN,leukocyte-IFN, omega-IFN, and the like. The term also includes amodified IFN such as one that is modified to include one or morepolyethylene glycol (“PEG”) molecules or a PEG-fatty acid moietyattached by covalent or non-covalent binding. Omega-IFN is preferred.

[0068] Typical suitable alpha interferons include recombinant interferonalpha-2b such as Intron-A interferon available from ScheringCorporation, Kenilworth, N.J., recombinant interferon alpha-2a such asRoferon interferon available from Hoffmann-La Roche, Nutley, N.J.recombinant interferon alpha-2C such as Berofor alpha 2 interferonavailable from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield,Conn., interferon alpha-n1, a purified blend of natural alphainterferons such as Sumiferon available from Sumitomo, Japan or asWellferon interferon alpha-n1 (INS) available from the Glaxo-WellcomeLtd., London, Great Britain, or a consensus alpha interferon such asthose described in U.S. Pat. Nos. 4,897,471 and 4,695,623 and thespecific product available from Amgen, Inc., Newbury Park, Calif., orinterferon alpha-n3, a mixture of natural alpha interferons made byInterferon Sciences and available from the Purdue Frederick Co.,Norwalk, Conn., under the Alferon Tradename or alpha interferon analogssuch as described in U.S. Pat. No. 6,204,022 and 5,939,286.

[0069] The term “interferon beta” or “beta-interferon” or “β-IFN” meansthe proteins described in U.S. Pat. No. 4,820,638 and 5,795,779.

[0070] The term “interferon gamma” or “gamma interferon” or β-IFN” meansthe proteins described in U.S. Pat. Nos. 4,727,138; 4,762,791;4,845,196; 4,929,554; 5,005,689; 5,574,137; 5,602,010; and 5,690,925.

[0071] The term “interferon tau” or “tau interferon” or “π-IFN” meansthe proteins described in U.S. Pat. Nos. 5,939,286; and 6,204,022.

[0072] The term “interferon omega” or “omega interferon” or ω-IFN asused herein means the species-specific protein that is described in U.S.Pat. Nos. 5,120,832 and 5,231,176. It can inhibit viral replication,cellular proliferation, and modulate immune response, even in settingsor patients where alpha interferon is not effective or has limitedeffectiveness. Omega-IFN is a naturally occurring interferon which haslimited homology to the alpha interferons (65%) and even less homologyto the beta interferons (35%), i.e., omega interferon is structurallydistinctive. Omega interferon appears to bind to what has been termedthe “α-β interferon receptor” as judged by in vitro testing. Usinggenetic engineering techniques, recombinant omega interferon ismanufactured in a form that is suitable for use in animals, includinghumans. It has been shown that antibodies developing in animals exposedto alpha interferon do not cross react with omega interferon, i.e., thatomega interferon is immunologically distinctive. Moreover, it has beendemonstrated in vitro in cells infected with the immunodeficiency virusthat the patterns of gene signaling induced by alpha and omegainterferon are different, i.e., that omega interferon is alsofunctionally distinctive.

[0073] The method may be used in any warm-blooded animal that has aninterferon-responsive disorder. The animals may be livestock, householdpets, or preferably humans. Thus, the method has both veterinary andhuman medicinal uses. Livestock treatable by this method include horses,cattle, swine, sheep, goats, and the like. Household pets include cats,dogs, rabbits, and the like. Preferably, however, the method of theinvention has its primary application in the treatment of humans, bothmale and female, young and old.

[0074] The diseases treatable by the method of this invention includethose of infectious (e.g. viral), immunologic, or proliferative originsthat in some portion of the population may be treatable by theadministration of an interferon. Diseases of viral origins are thosecaused by a virus such as those set forth in Stedman's MedicalDictionary, 26^(th) Edition, particularly hepatitis B, C, or D,especially hepatitis C. Immunologic diseases are those of where theimmune system of a patient is unbalanced. These diseases include, forexample, chronic granulomatous disease, acquired immunodeficiencysyndrome, multiple sclerosis, systemic lupus erythematosus, andscleroderma. Proliferative diseases are generally those that includevarious types of malignant neoplasms, most of which invade surroundingtissues and may metastasize to several sites. These are often referredto as cancers and include, e.g., condyloma accuminata, hairy cellleukemia, malignant melanoma, multiple myeloma, follicular lymphoma,non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, chronic myelogenousleukemia, basal cell carcinoma, carcinoid syndrome, superficial bladdercancer, renal cell cancer, colorectal cancer, laryngeal papillomatosis,actinic keratosis, or AID's related Kaposi's sarcoma. Otherproliferative diseases include fibrosis of tissues or organs such as thelung or liver. Tuberculosis is also treatable by the method of thisinvention.

[0075] In carrying out the method of treatment of this invention, a drugformulated for short-term use is administered to a patient in needthereof and is adjusted to improve the therapeutic index . Thisadjustment may be done in one or a plurality of patients usingmeasurements well known in the art to show the drug is workingtherapeutically and whether there are known or suspected side effects.The term “short-term use” means that the drug is used as a formulationdesigned to be delivered to a patient multiple times to obtain thedesired effect. For example, the drug may be delivered by injections,infusion, implant, transdermally, orally, parenterally, or byinhalation. For example, an interferon may be delivered intravenously,intramuscularly, or subcutaneously once every 6 hours, 12 hours, or 24hours. Such dosing will generally show a concentration profile similarto that shown in FIG. 3. By changing the dosage frequency the amount inthe blood may change as shown in FIG. 4. The dosage used over the shortterm is then adjusted to maximize the therapeutic effect and minimizethe adverse side effects. The dosage has two components: the dose leveland the dose rate. The dose level is the total amount of drug deliveredto a patient, while the dose rate is the amount delivered to the patientper time unit.

[0076] For example, if omega interferon is administered by a standardroute (e.g. IV, IM, subcutaneous), the following important parametersare useful to maximize the therapeutic response while minimizing theadverse side effects and select a safe, tolerable, and effective dosefor long-term administration of omega interferon in patients withchronic hepatitis C (“HCV”): number of target cells, rate constant fordeath of target cells, rate of production of target cells, fractionalreduction in de novo rate of infection of target cells, rate constantfor de novo infection of target cells, viral load (i.e. HCV RNA levels),number of productively infected cells, rate constant for death ofinfected cells, fractional reduction in production of virions byinfected cells, rate of production of virions by infected cell, rateconstant for clearance of hepatitis C virions. These are described inmore detail hereinafter.

[0077] Referring to FIG. 1, one sees a graph showing the change in HCVRNA levels versus time in individual subjects with chronic HCV infectionresistant to 3-12 months of treatment with alpha-IFN, with or withoutRibavirin. Each patient was treated short-term for various periods oftime with 15 μg/dose of omega-IFN, with 3 doses per week on days 1, 3,and 5 of each 7 day week (both ordinate and abscissa linear scale) Threeof 8 patients manifested undetectable HCV RNA after treatment with omegainterferon. In resistant patients it appears that the maximal decreasein viral load may be apparent within the first few days of treatment,potentially as early as two days after the commencement of treatment.The tolerability and safety profile is reasonably well establishedwithin 4 weeks after beginning treatment.

[0078] In FIG. 2, a graph is presented that shows an increase in theresponse rate as measured by complete viral clearance in human patientswith chronic HCV infection previously untreated with an interferon. Eachpatient was treated short-term for various periods of time with 15μg/dose of omega-IFN, with 7 doses per week for 2 weeks then 3 doses perweek on days 1, 3, and 5 of each 7 day week thereafter. The tolerabilityand safety profile is reasonably well established within 4 weeks afterbeginning treatment.

[0079]FIG. 3 presents a graph showing the pharmacokinetics of omega-IFNafter a short-term dose of omega-IFN in humans. The median half-life ofabsorption is 3.1 hours, while the median half-life of elimination is11.4 hours.

[0080] Turning now to FIG. 4, one sees a graph showing a calculatedpharmacokinetic profile of omega-IFN with once daily (q 24 hour) and 4times daily (q 6 hour) dosing cycles, with the same daily dose of 15 μg.With 4 times daily dosing the variation in omega plasma levels fromtrough (approximately 28.1 pg/mL) to peak (approximately 29.9 pg/mL) isapproximately 6% of the peak value. From the mid-range value ofapproximately 29 pg/mL, the variation to peak or to trough isapproximately 3%. Such a small variation is effectively a steady-stateand is achieved within 72 hours after the commencement of dosing withomega interferon. The variability can be reduced to even smaller valuesby reducing the dose and increasing the frequency of administration.This steady-state pattern effectively replicates that which would beobserved with a long-term delivery system emitting an interferon at afixed rate, where the rate was adjusted to achieve the plasma level asshown.

[0081] With the information shown in FIGS. 1-4 and other information,one can adjust the dosage of the short-term formulation to increase andpreferably maximize the therapeutic effect and decrease and preferablyminimize the adverse side effects and select a dosage to be deliveredover the long-term, i.e. from a month to a year or more, using along-term delivery formulation that delivers the drug at a controlledrate over time. While it may be desirable to commence long-term therapyimmediately upon cessation of short-term therapy, such immediatetransition is not always required and there may be a delay of days tomonths in commencing long-term therapy. In this method, the interferondelivered in the short term is generally the same as the interferon thatwill be delivered to the patients over the long-term, although aninterferon that differs from that given for the short-term may beadministered over the long term. Once a formulation for short-termadministration is established, the same, or essentially the sameformulation, may be used for long-term administration, albeit packagedfor long-term controlled releases. Alternatively, the long-termformulation may be different to account for the needed changes for thelonger, controlled-release characteristics. In some cases, if theattending physician believes it appropriate, more than one interferon oreven different interferons (e.g., alpha interferon and pegylated alphainterferon) may be used for the short-term or long-term administration,with each interferon being formulated the same or each formulateddifferently. If useful, the dosage can be adjusted upward byadministering a long-term formulation that provides a fraction of thedosage rate released by the first long-term formulation. Long-termformulations that are useful for delivering the desired dosage over timeinclude any formulations or devices that aid in the delivery of the drugin a controlled manner to the patient at the rate desired. Theseformulations may be internal (i.e. implantable in the patient to deliverthe drug internally) or external (i.e. delivers the drug internally withthe formulation located external such as a pump or chronic intravascularinfusion system or transdermal system) to the patient. While oral orinhalation devices may be used, they don't lend themselves to easylong-term use. If internal (implantable or injectable) the formulationmay be bioerodible, e.g., a gel or pellet, or nonbioerodible, e.g., amechanical device such as a pump.

[0082] An example of a suitable nonbioerodible formulation or device isone employing the DUROS® system (ALZA Corporation), which is a miniaturedrug-dispensing pump currently made principally from titanium and whichcan be as small as a wooden matchstick.

[0083] The DUROS® pump operates like a miniature syringe loaded with adrug inside the drug reservoir. Through osmosis, water from the body isslowly drawn through a semipermeable membrane into the pump by a salt orother suitable osmotically active substance residing in the enginecompartment. This water is absorbed by the osmotic substance which thenswells and which slowly and continuously pushes a piston, dispensing thecorrect amount of drug out the drug reservoir and into the body. Theosmotic engine does not require batteries, switches or otherelectromechanical parts in order to operate. The amount of drugdelivered by the system is regulated by many factors, including, forexample, the materials used in manufacturing, the membrane's controlover the amount of water entering the pump, the strength of the osmoticagent, the frictional resistance to motion of the piston, the size andshape of the reservoir, the size, shape, and length of the orifice(s)through which the drug(s) exit the pump, the formulation and type of thedrug(s) and whether the formulation is a liquid, suspension, or gel, andpressures generated within the device to expel drug(s) orcounter-pressures generated in the tissues that resist such expulsion.

[0084] Other useful long-term delivery formulations may be preparedusing the ALZET® technology developed by the ALZA Corporation. Theseformulations may be delivered externally. The details of the ALZETtechnology may be found at www.alzet.com.

[0085] Patents that provide useful guidance in preparing long-termdelivery devices that may be useful in the methods and kits of thisinvention include those which are assigned to Alkermes. Other patentsinclude those assigned to ALZA Corporation (now a subsidiary of Johnsonand Johnson, Inc.), particularly relating to their “DUROS®” technology.Representative patents useful for the various aspects of this inventioninclude the following U.S. Pat. Nos.: 5,529,914; 5,858,746; 6,113,938;6,129,761; 5,985,305; 5,728,396; 5,660,847; 5,112,614; 5,543,156;5,443,459; 5,413,572; 5,368,863; 5,324,280; 5,318,558; 5,221,278;4,976,966; 4,917,895; and 4,915,954. All are incorporated herein byreference.

[0086] The method of treatment, e.g. of HCV, can be further visualizedwith reference to FIG. 5. The figure is divided into a short-termformulation dosing period and a long-term formulation dosing period.During the short-term formulation dosing period the dose level of omegainterferon is adjusted to assess both initial antiviral response (shownhypothetically in the graphs of HCV RNA and liver enzymes over time)along with safety and tolerability. The IFN dose is adjusted to achievemaximal antiviral effects with acceptable safety and tolerability. Thisprocess is represented by the series of stepped boxes showing a maximumdose with a slight reduction. With the dose identified the patient isthen maintained on the dose during a transition, after which thelong-term formulation dosing takes places. The short-term formulation isdelivered first, and the long-term formulation is subsequently deliveredeither with or without an overlap of dosing with the short-term andlong-term formulations. If there is no overlap, the delivery of thelong-term formulation may be deferred for very brief periods of time(seconds to days) or longer periods of time (a week to several months).The long-term delivery is done with a long-term formulation and one ormore fractional modules (or several fractional modules). The patient ismonitored for the suppression of viral replication (as shown by thehypothetical graphs of HCV RNA and liver enzymes over time) as well asthe prevention of long-term adverse sequelae of HCV infection includingcirrhosis and liver cancer. The long-term treatment may be adjusted upwith another equipotent formulation or a fractional module dosage formor may be adjusted down by providing one or more fractional moduledosage forms after the device ends administration. Preferably acontrolled-release dosage per time unit selected for long-termformulation is about equivalent to the dosage release over a time unitfor the short-term formulation. For example, if the short-termadministration is 30 mg in 24 hours, then the long-term formulationwould be designed to release about 1.25 (30 ÷24 =1¼)μg/hour. On theother hand, the long-term dosage per unit of time may be more or lessthan the short-term administration.

[0087] Individualizing Doses

[0088] Another aspect of the invention is a method for individualizingdoses of a drug delivered over an extended period of time to a patientin need of such treatment. This is particularly valuable for patientsreceiving implantable devices. The method is particularly useful forinterferon, especially omega interferon. For example, the methodcomprises determining the most commonly identified optimal dosage (i.e.the dose-level or dose-rate) in a sufficiently large population ofrecipients to define a unit dosage; and subsequently, using a long-termformulation for controlled release, administering at least oneunit-dosage optionally with one or more fractional unit dosages, suchthat, in aggregate, the optimal dosage identified during dosing with theshort-term formulation can be approximated with theunit-dosage/fractional unit-dosage combination using the long-termformulation. The desired dosage is selected for long term delivery andthereafter administered with the long-term delivery formulation, whichcan be optionally subsequently adjusted, if necessary, to furthermaximize therapeutic response with simultaneously minimizing adverseside effects. This is discussed further under “Dosimetry Protocol.” Theprinciples expressed in the Method of Treatment section apply the methodfor individualizing doses.

[0089] Convenient fractional unit-dose devices can be selected from 0.1,0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9. Smaller or larger values lessthan 1.0 can also be selected. With one unit-dose formulation and onefractional unit-dose module, e.g., 0.4, it is possible, by using one ortwo of these items, to attain doses of 0.4, 0.8, 1.0, 1.4 and 2.0unit-doses. With one unit-dose formulation and two fractional unit-dosemodules, e.g., 0.3 and 0.5, it is possible, by using one, two or threeof these systems, to attain doses of, e.g., 0.3, 0.5, 0.6, 0.8, 0.9,1.0, 1.1, 1.3, 1.5, 1.6, 1.8, 2.0, 2.3, 2.5, and 3.0 unit-doses. With anincrease in the number of available fractional unit-dose modules ofdiffering fractional values and/or an increase in the number of systemsthat can be utilized, it is possible to achieve any target number ofunit-doses. In this manner, it is possible to individualize the doseduring long-term therapy based on the results from the short-termtherapy period.

[0090] However, even if the short-term formulation and dosing-regimenmatching is not optimal when compared to that expected with thelong-term formulation and long-term delivery system, the use of a first,short-term formulation, whether recently or in the past, willnonetheless facilitate recognition of useful antiviral effects (in thecase of hepatitis C) and the recognition of adverse effects that appearearly during the course of therapy with an interferon. It will also helpto prevent the premature selection of a dose or dose-rate with thelong-term delivery system that is too low to be effective or too high tobe safe and tolerated.

[0091] If the short-term formulation is delivered in such a manner thatthe delivery characteristics match very closely those of the long-termformulation and attendant long-term delivery system, then the total doseper day, per week or per month (or for any other convenient unit oftime) found to be effective, safe, and tolerated using the short-termformulation, can be prepared for the long-term formulation. Thoseskilled in the art will recognize that this process of doseapproximation will apply to chemically modified or unmodified, andglycosylated or nonglycosylated (or both) interferons or otherinterferon-like proteins that have interferon activity.

[0092] Method of Manufacturing

[0093] Another aspect of the invention is a method of manufacturing adelivery system for delivering a drug, such as omega-IFN, over time in acontrolled manner. The method comprises preparing a long-term deliverydevice designed for delivery of a drug at a relatively constant rateover time, the rate being determined to be a standard dosage ratedesigned for a patient to receive a standard dosage amount over a unitof time to treat a disease state in the patient treatable over time bythe drug, and preparing a plurality long-term delivery system designedfor delivery of the drug at a relatively constant rate over time, whichrate for each module is a fraction of the standard dosage rate. Morethan one unit dose or more than one fractional dose may be selected.Each system is suitable for presentation to a patient in need thereofalone or in combination with an identical system or a long-termformulation delivering the standard dosage rate, depending on the dosagerate or fractional dosage rate determined to be appropriate for thepatient.

[0094] By way of specific example, a short-term formulation of omegainterferon is administered to a patient with chronic HCV for one or twoweeks. The weekly dose may range from 22.5 to 360 μg. The patient isevaluated for the presence of adverse symptoms, signs, or laboratoryparameters. The level of HCV RNA is also measured. Laboratory parameterswill usually include a measure of the white blood cell count, along witha white blood cell differential, so that the number of granulocytes canbe determined. If HCV RNA levels have declined, preferably toundetectable levels, but the granulocyte count falls to less than 1000cells/mm3, then the dose of omega interferon can be reduced by, forexample, one-third or one-half. The HCV RNA level and granulocyte countare again monitored and when the granulocyte count returns to, forexample, at least 2000 cells/mm³ and the HCV RNA level is judged to bestill satisfactorily reduced, then the long-term dosing system isinjected or implanted without delay. The dose in the long-term deliverysystem is selected to suitably approximate the short-term dosepreviously shown to be effective and acceptably safe.

[0095] By way of another specific example, a short-term formulation ofomega interferon is administered to a patient with chronic HCV for 4months. There are no significant acute side effects and HCV RNA levelshave been reduced by more than 99.99%. After 4 months of treatment, thepatient becomes depressed. The depression is unresponsive toconventional oral antidepressants and the patient becomes suicidal.Omega interferon is temporarily stopped. The use of the short-termformulation facilitates a more rapid offset of action. The patient ishospitalized and receives electroshock therapy. Suicidal ideation ceasesand depression remits. Omega interferon therapy is resumed at a lowerdose using the short-term formulation. Depression does not reappear, HCVRNA levels are still reduced (more than ⁹9%) and 4-6 months afterwardsthe long-term delivery system is selected to suitably approximate thenew, reduced dose now shown to be effective and well tolerated.

[0096] By way of a third specific example, a patient with chronic HCV istreated for 6-12 months with a short-term dosing form of an alphainterferon (whether or not pegylated, with or without oral ribavirin).After one year of treatment with the alpha interferon regimen, HCV RNAlevels have been reduced by approximately 80% but are still detectable.Treatment with the alpha interferon regimen is halted. 1-12 monthslater, omega interferon is administered for two weeks using a short-termdosing form, and suitable laboratory and clinical tests are conducted todemonstrate viral responsiveness to therapy in the absence ofunacceptable acute side effects.

[0097] The system can be viewed then as a kit that can be used by thedoctor or other provider of health care to individualize the dosage ratefor a patient over time depending on the patient's characteristics suchas age, gender, size, health condition, etc. The most commonlyprescribed dose or dosage rate can be viewed as the median or “standard”or “unit” dosage. However, for a person who is physically of lower bodymass than the median body mass for all patients, a the use of twodelivery systems, each giving about 40% of the “unit” dosage rate, maybe appropriate, i.e. a total of 80%, while a person with a body masssubstantially higher than the median may require 140% of the unit dosagerate, e.g. a unit dose system plus a second system releasing at 40% ofthe unit dose rate.

[0098] The Kit

[0099] Still another aspect of this invention is a kit useful fordelivery of a relatively constant amount of a drug thereof over time,wherein the amount of drug delivered to an individual patient within apopulation can be adjusted to the patient's individual needs fortreatment. The kit comprises at least one long-term delivery formulationdesigned for delivery of a drug at a relatively constant rate over time,the rate being determined to be a unit rate as a standard dosage totreat a disease state in a patient in the population over time, and atleast one long-term delivery system or device designed for delivery ofthe same drug at a relatively constant rate over time, which rate is afraction of the standard dosage rate. Each formulation in the kit issuitable for presentation to a patient in need thereof alone as astandard dosage formulation or a fractional amount thereof.

[0100] The kit can also comprise a combination of two or more identicalsystems, depending on the dosage rate determined to be appropriate forthe patient.

[0101] The kit can also comprise at least two or more long-term deliverydevice designed for delivery of the same drug at the same or different(yet relatively constant) rates over time, for which each rate is afraction of the standard dosage rate, wherein each device in the kit issuitable for presentation to a patient in need thereof alone or incombination with an identical module or the other standard device,depending on the dosage rate determined to be appropriate for thepatient.

[0102] The kit can also comprise a combination of a short-termformulation with a delivery device or system therefor and one or moreidentical or different long-term delivery systems containing thelong-term formulation.

[0103] For example, different kits are shown in the table below:Short-term dosing form (number of days) none 7 14 90 Long-term dosingform 0.4 1.0 1.0 1.0 #1 (units) Long-term dosing form 0.4 none 1.0 0.1#2 (units) Long-term dosing form none none none 0.1 #3 (units) totallong-term units 0.8 1.0 2.0 1.2

[0104] The examples in the table are non-limiting, and those skilled inthe art will recognize that other combinations are possible.

[0105] Both the method of manufacture and the kit aspects of theinvention preferably will include a further refinement. This is thepresence of written dosing instructions. The dosing instructions are foradjusting the rate of administration of the drug by employing one or acombination of devices to achieve the desired release rate of the drugfor an individual patient depending on the patient's needs over time.

[0106] For example, in addition to the long-term dosing system(s)contained in the kit, with or without short-term dosing systems, the kitmay also include written dosing material may describe the use of omegainterferon, or other interferon, in an immunodiagnostic orimmunotherapeutic protocol to determine the appropriate short-term andlong-term dosing. Other factors to be considered in the protocolcomprise the medical disorder to be treated and, in the case of viralhepatitis C, the patient or viral factors that may affect responsivenessto an interferon, e.g., viral subtype and viral load as well ascharacteristics of the patient comprising age, sex, weight, height, raceor ethnicity, genetic profile comprising single nucleotide polymorphismsor haplotypes, the duration and severity of the medical disorder, thepresence and severity of hepatic injury, concomitant illnesses,concomitant medications and the like.

[0107] For example, written material can be applied directly to acontainer (such as by the application of a label directly to a vialcontaining the interferon with or without carriers or excipients).Alternatively, a container-closure system holding the interferon can beplaced into a second container, such as a box, and the written material,in the form of a packaging insert, can be placed in the second containertogether with the first container-closure system holding the interferon.

[0108] The written portion may describe indications for prescribing thedrug, e.g., an interferon such as omega interferon, either asmonotherapy or as part of combination therapy with one or more otherinterferons, with one or more non-interferons, or a combination ormixture of other drugs. Such indications would include aninterferon-responsive disorder (for example, viral hepatitis C). Thewritten material should further describe that the interferon or otherinterferon, as monotherapy or part of a combination therapy regimen, isuseful for the treatment of, for example, viral hepatitis C.

[0109] In a preferred embodiment of this invention, the written materialwill describe omega interferon as the interferon to be used intreatment. In a most preferred embodiment, the written material willdescribe that omega interferon is used in the treatment of viralhepatitis, in particular viral hepatitis C and viral hepatitis B.

[0110] In other embodiments, the written material may describe that theinterferon is of a recombinant form, manufactured in bacterial cells(and therefore usually nonglycosylated) or manufactured in mammaliancells (and therefore usually glycosylated). The written material willalso describe whether the interferon is chemically unmodified or hasbeen chemically modified by the addition of, for example, polyethyleneglycol moieties of various lengths and at various sites of attachment tothe interferon. The written material will also describe how toadminister the long-term formulation or module.

[0111] Still further, it can be described in the written material thatthe appropriate dose to establish the initial safety, tolerability, andefficacy profile of the short-term formulation is provided byadministering, on average, 1-210 μg per week of omega-IFN, and in a morepreferred embodiment 9-60 μg per week. The written materials willdescribe the protocol to be followed to adjust the initial dose inresponse to observed events relevant to safety, tolerability, andefficacy of the interferon. The written materials will also referenceone or more long-term delivery systems containing an interferon and theprotocol for selecting the dose or dose-rate to be delivered by saidlong-term delivery system containing or used with the related long-termformulation.

[0112] The written material would preferably be provided in the formrequired by the regulatory agency with jurisdiction over the approvalfor marketing of such an interferon, such as the United States Food andDrug Administration, in the form of a package insert for a prescriptiondrug. The written material would indicate that the interferon would beprescribed for use in patients having an interferon-responsive disorder.In a preferred embodiment, the written material would indicate that theinterferon is omega interferon and that the interferonresponsive-disorder is viral hepatitis, in particular viral hepatitis C.The written material would indicate that the interferon is useful asprimary or secondary treatment or in combination with other treatments.It would further describe that while the interferon has an effect on theinfected liver in patients with viral hepatitis C that the interferonalso may reach other tissues where it may have no therapeutic effect.

[0113] Principal toxicities could also be described and could include,by way of example, headache, flu-like symptoms, pain, fever, asthenia,chills, infection, abdominal pain, chest pain, injection site reaction(as appropriate), malaise, hypersensitivity reaction, syncope,vasodilatation, hypotension, nausea, constipation, diarrhea, dyspepsia,anorexia, anemia, thrombocytopenia, leukopenia, other blood dyscrasias,myalgia, arthralgia, insomnia, dizziness, suicidal ideation, depression,impaired ability to concentrate mentally, amnesia, confusion,irritability, anxiety, nervousness, decreased libido, urticaria,alopecia, and others.

[0114] It may further be described in the written material that whensymptoms such as fever, chills, or flu-like manifestations are observedthat these can be treated with Tylenol®, antihistamines such asBenadryl®, and that hypotension may respond to the administration offluids or pressor agents or, if the symptoms or signs are sufficientlysevere, that the dose should be reduced or treatment terminated.

[0115] The written material may also describe that delivery of theformulation of the interferon intended for short-term administration isby injection, infusion, inhalation, oral or transdermal administration.The preferred embodiment is by injection or infusion and the mostpreferred is by injection. Warnings, precautions, and contraindicationsshould be described.

[0116] Example of a Dosimetry Protocol

[0117] In treating a disease such as hepatitis C, antiviral effects fromadministration of an interferon may become obvious within hours orwithin a few days. Accordingly, in order to begin the assessment of thesafety, tolerability, and effectiveness of the short-term formulation ofthe interferon, it is informative to utilize a short-term dosimetryprotocol to assess antiviral effects. This protocol is a furtherelucidation of the invention.

[0118] At baseline (preferably within 1 hour prior to the initiation ofdosing with the short-term formulation) and at, preferably, 8 and 14days after dosing has begun, chemistry, hematology, and liver functiontesting are performed. Samples for hepatitis C viral ribonucleic acidlevels (HCV RNA) testing are then obtained at baseline and againpreferably at 2, 4, 7,10, 14, 19 and 24 hours after dosing on Day 1 (theinitial dose of interferon); at 5 and 10 hours after dosing on Day 2;and immediately prior to the daily omega interferon dose on Days 3, 4,5, 6, 8, 10, 12 and 14 of dosing. Similar tests can then be performed,if required, at 2-4 weeks intervals while viral response and safety andtolerability are being assessed while the short-term formulation isbeing administered. Most preferably, this assessment is performed usingomega interferon.

[0119] Responsiveness to treatment can be assessed by variousparameters, ranging from

[0120] a lack of detectable HCV RNA (viral load is below the lower limitof detectability for the assay being used) or

[0121] a decrease in HCV RNA level to less than a preselected percentageof baseline viral load, e.g., 50% of pretreatment level,

[0122] a decrease in a liver enzyme such as alanine amino transferase(ALT) to normal or to less than a preselected percentage of baselineviral load, e.g., ⁵⁰% of pretreatment level or

[0123] histopathological changes as assessed by liver biopsy.

[0124] Dosing at different levels and for variable periods of time maybe necessary to establish an adequate safety, tolerability, and efficacyprofile (i.e. maximize therapeutic response and minimizing adverseeffects) for the short-term formulation and to enhance the predictivepower of the information acquired during the use of the short-termformulation. The duration of such assessments could be as short as oneday but preferably such assessments are made for at least one week, morepreferably for two to four weeks, and most preferably for four to eightweeks.

[0125] Assessment of antiviral response or measurement of changes inliver function tests may necessary in order to select a dosage (i.e.dose-level or dose-rate level) intended for long term administrationfrom a long-term delivery system. Very rapid assessment of antiviraleffects in patients with hepatitis C can now be accomplished asdescribed below. The invention is not limited by the particular viralpharmacodynamic model, doses, time or time intervals, or factors to beconsidered in the application of a particular model. Although assessmentof antiviral response is preferable to occur within no more than days ora few weeks of initiating long-term therapy, the current inventionencompasses the possibility that initial antiviral assessment may haveoccurred weeks, months, or possibly a year or more prior to theinitiation of long-term treatment.

[0126] Description of Modeling of Viral Kinetics

[0127] To model the kinetics of hepatitis C viral kinetics duringtreatment with omega interferon, we have used a standard model of viralinfection described by the differential equations:

dT/dt=s−dT−(1−η)βVT

dI/dt=(1−η)βVT−δI

dV/dt=(1=ε)pI−cV

[0128] where the terms are defined as shown in the table below:Definition of Terms T Number of target cells t Time d Rate constant fordeath of target cells s Rate of production of target cells η Fractionalreduction in de novo rate of infection of target cells β Rate constantfor de novo infection of target cells V Viral load I Number ofproductively infected cells δ Rate constant for death of infected cellsε Fractional reduction in production of virions by infected cells p Rateof production of virions by infected cell c Rate constant for clearanceof virions

[0129] If it is assumed that initially η=0 and that the number ofproductively infected cells remains relatively constant for the firsttwo days of therapy, then the viral load (V) at time t, V(t), is

V(t)=V ₀[1−ε+εexp(−c(t−t ₀))]

[0130] The parameters ε and c can be estimated, among others, for eachpatient using nonlinear regression analysis to fit the above equation tothe HCV RNA levels measured for the 48 hours after initiation of omegainterferon dosing. Using those parameter values calculated for eachpatient and assuming the number of target cells remains relativelyconstant over the two weeks of therapy, nonlinear regression analysiscan also be used to estimate the parameter 6 for each patient using theequation

V(t)=₀ {Aexp[λ₁(t−t ₀)]+(1−A)exp[−λ₂(t−t ₀ )]}

[0131] where

λ_(1,2) ={fraction (1/2)}{( c+δ)±[(c−δ ²+4(1−ε)cδ] ^(½)}

A=(εc−λ ₂)/λ₁−λ₂)

[0132] Fitting these equations to the data obtained in clinical testingwith two different doses of omega interferon in patients withalpha-interferon resistant hepatitis C, we have estimated the followingvalues for the key parameters of antiviral effect, ε and C. Mean Value15 □g/day 30 □g/day Parameter (n = 7) (n = 4) ε .75 .78 c 7.25 day⁻¹3.10 day⁻¹

[0133] These findings indicate that, on average, there is a 75-78%reduction in virion production by infected cells and that the rateconstant for virion clearance increases with increasing dose, i.e., thatthe time required for a given clearance level is decreasing.

[0134] The analysis of data from a clinical study of the type describedin patients with viral hepatitis C can estimate the activity of severaldoses of interferon and the time-course and mechanism(s) of antiviralactivity. The model parameter measuring initial antiviral activity is ε,the fractional reduction in the production of virions by infected cells.For any group of patients treated at one dose level, it is possible todetermine the group range, median, and mean (with 95% confidenceinterval by Normal approximation) for ε. The same group of patients canthen be treated at a different dose level and the antiviral effectscompared within and between patients. The data from this type of studycan be used to guide the selection of dose(s) to be administered duringlong-term treatment.

[0135] It is possible to perform the multiple pairwise comparisons of εcalculated for the multiple dosing groups of patients. For each pair ofgroups it is possible to report the difference in mean ε (with 95%confidence interval by Normal approximation) and median ε (with 95%confidence intervals).

[0136] As an additional evaluation of possible antiviral activity, it ispossible to examine the percent change in serum HCV RNA, alanine aminotransferase (ALT) and aspartate amino transferase (AST) from baseline tothe end of therapy for each patient, as well as the group medians andmeans (with 95% confidence intervals by Normal approximation).

[0137] The relationship baseline ALT levels and initial viral load to εand relationship of baseline ALT and initial viral load to δ can beassessed using appropriate statistics. All changes in physicalexaminations, all adverse events and any significant changes inlaboratory parameters can be assessed and compared, if need be, betweendifferent dosing groups or between different dose levels or dose ratesfor the same patient.

[0138] Such effects after administration of a short-term formulation canbe determined over a short period of time measured in hours to days tolonger periods of time, measured in days to weeks or, if necessary, evenweeks to months before selecting the long-term dose or dose-rate andchanging from administering the (first) short-term formulation toadministering the (second) long-term formulation, whether a singleformulation or a combination of modules.

[0139] In one embodiment, dosing with an interferon is performed atintervals ranging from 2 to 24 hours in order to establish a targetsteady state blood or tissue level. Dosing at this frequency may bemaintained for 1 to 3 or more days after which dosing frequency may bereduced at the discretion of the health care provider.

[0140] The object of the administration of the short-term formulation isto determine a generally effective and generally safe and tolerateddose, i.e. to improve the therapeutic index. This object can be achievedby step-wise adjustments in the dose of interferon delivered with theshort-term formulation. Dosing can be initiated at what is believed tobe a low or even ineffective dose and escalated at regular or irregularintervals. Dosing escalation can continue until a poorly tolerated doseis reached or until a maximally effective dose is reached (based onantiviral effects and desirable changes in liver function tests). Thendosing can be stabilized or reduced moderately and then stabilized totest the effectiveness and tolerability of the chosen dose level ordose-rate. See FIG. 5 for a visual representation of this sequence ofevents.

[0141] The dose to be delivered with the long-term formulation can beadjusted to match the most generally effective and generally safe andtolerated dose as determined by use of the short-term formulation duringthe short-term formulation treatment period. To maximize the utility ofthe data from use of the short-term formulation, the dose, dose intervaland dosing frequency of the short-term formulation is preferablyadjusted to produce a drug delivery profile that matches as closely aspossible that which is to be delivered by the long-term formulation.

[0142] The following examples of the present invention are provided toillustrate the invention in more detail. The examples are to be taken asillustrative only, without limiting the scope of the invention.

EXAMPLE 1

[0143] Omega Interferon in a Short-Term Formulation Followed by OmegaInterferon in a Long-Term Formulation Suitable for Use in anImplantable, Non-Erodible Drug Delivery Formulation

[0144] Preparation and Administration of Omega Interferon in aShort-Term Formulation

[0145] Omega interferon is produced by standard genetic engineeringtechniques in E. coil bacteria or in mammalian Chinese hamster ovarycells. Such techniques are further described for interferons generallyin U.S. Pat. No. 4,727,138 and more specifically for omega interferon inU.S. Pat. Nos. 5,120,832 and 5,231,176. The interferon is then purifiedand used immediately or frozen and then subsequently thawed for use. Theinterferon may be lyophilized with appropriate stabilizers forsubsequent reconstitution with water-for-injection or other suitablesolvent or the interferon may be prepared for use initially as a liquidformulation.

[0146] For a lyophilized preparation of omega interferon 33 μg of omegainterferon (measured by the amount of protein present) is prepared alongwith, by way of example, human serum albumin 25% (5 mg), potassiumchloride (0.2 mg), potassium dihydrogen phosphate (0.2 mg), sodiumchloride (8.0 mg). This lyophilized preparation is maintained at 2-8° C.and then reconstituted with 1 mL of sterile water-for-injection. Asknown to those skilled in the art, other formulations are possible.

[0147] For a liquid formulation of an interferon, the interferon isdissolved in 1 mL sterile water-for-injection which can also containsodium chloride (7.5 mg), sodium phosphate dibasic (1.8 mg), sodiumphosphate monobasic (1.3 mg), edetate disodium (0.1 mg), polysorbate 80(0.1 mg), and m-cresol (1.5 mg) as a preservative, among otherexcipients known to those skilled in the art.

[0148] This short-term formulation is then administered by subcutaneousor intramuscular injection or by bolus intravenous injection or byinfusion, preferably by subcutaneous injection.

[0149] A formulation for long-term use is dependent upon the long-termdelivery formulation. For a non-erodible implant, a suitable formulationwill be stable at the body temperature of warm-blooded animals for theduration of the dose contained by or within the system. It has beendemonstrated that an interferon remains chemically stable and active ina perfluorocarbon solvent such as perfluorodecalin. Non-erodibleimplantable systems suitable for use in delivery of a long-termformulation are described in U.S. Pat. Nos. 4,976,966, 5,112,614,5,66,0847, 5,728,396, 5,985,305, 6,113,938, which are incorporatedherein by reference.

[0150] After determination of a safe, tolerated and effective dose usingthe first, short-term formulation, preferably wherein the selection wasmade by replicating the pharmacokinetics of delivery of the long-termsystem using the short-term formulation and appropriately selected dosesand dosing intervals, the long-term dose and dose-rate are selected. Oneskilled in the art will know that it is then necessary only to load thelong-term delivery system with the predetermined total dose.

[0151] Alternatively, a generally safe and effective total dose per unittime is established for a population of animals with aninterferon-responsive disease using the short-term formulation. The mostpreferred interferon is omega interferon. The most preferredinterferon-responsive disease is viral hepatitis C. The unit of time maybe conveniently selected from day, week, month, or quarter-year.

[0152] The preferred unit of time is chosen with regard to factors thatcomprise the maximal delivery period of the selected long-term deliverysystem, the most reliable delivery period for a selected long-termdelivery formulation, the particular interferon, the stability of theinterferon in the long-term formulation.

[0153] For the convenience of humans to be treated with the currentinvention, the preferred unit of time for the drug to be delivered overthe long-term in the long-term formulation is either the month orquarter-year and the most preferred is the quarter-year. This gives thephysician an opportunity to review progress in the patient and tocontinue long-term treatment as needed.

[0154] Unit Dose and Fractional Unit Modules

[0155] The total dose for the selected unit of time is then selected asthe “unit-dosage” for the long-term delivery system. In the case of animplantable, non-erodible delivery system, the system may also be loadedwith fractional unit doses. In the case of bio-erodible systems, eitherlesser volumes of the bio-erodible system are utilized or fractionalamounts of the unit-dose are loaded into or onto the system.

[0156] In the case of viral hepatitis C, the preferred unit-dose perquarter-year is 300-8100 μg of omega-IFN. A more preferred unit-dose perquarter-year is 300-5040 μg and the most preferred unit-dose perquarter-year is 630-2520 μg.

[0157] Those skilled in the art will understand that with a unit-doseand, if desired, one or more fractional unit-dose module, the long-termdose can be individualized for an animal with an interferon-responsivedisorder and to achieve a practical matching of the long-term dose withthe dose determined from the previous use of the short-term formulation.

[0158] Those skilled in the art will recognize, however, that forpractical purposes in the therapy of interferon-responsive disorders, arange of unit-doses will be safe, tolerated, and effective, thusminimizing the need for excessively numerous fractional unit-dosemodules. Moreover, if the unit-dose is well chosen and based on datafrom a sufficiently large number of humans with interferon-responsivedisorders, then it is possible to minimize further the need for a largenumber of long-term unit-dosage formulations or fractional unit-dosemodules. Notwithstanding the foregoing, with knowledge of the results ofthe use of the short-term formulation, a unit-dose system (i.e. thelong-term formulation) used with or without one or more fractionalunit-dose modules provides great flexibility in the selection of dose,individualization of long-term dosing and optimization of long-termdosing.

EXAMPLE 2

[0159] Omega Interferon in a Short-Term Formulation Followed by OmegaInterferon in a Long-Term Formulation Suitable for Use in an Implantableor Injectable Erodible or Dispersible Drug Delivery System

[0160] Omega interferon is prepared for short-term use as described inEXAMPLE 1.

[0161] Erodible or dispersible implantable or injectable drug deliverysystems suitable for use in the long-term delivery of an interferon,including omega interferon, include such systems as described in U.S.Pat. No. 5,543,156, which is incorporated herein by reference, as wellas in U.S. Pat. Nos. 5,529,914, 5,858,746, and 6,129,761, which are alsoincorporated herein by reference.

[0162] Those skilled in the arts will recognize that the currentinvention can be utilized to optimize or improve the long-term treatmentof warm-blooded animals with any interferon-responsive condition andwith any interferon or interferon-like molecule suitable for short-termformulation or suitable for long-term formulation with an appropriatelychosen long-term delivery system, and whether employed as monotherapy oras part of a combination therapy regimen.

[0163] All articles, patents and other information cited herein areincorporated by reference for all purposes.

The subject matter claimed is:
 1. A method for the treatment of an interferon-responsive disorder in a warm-blooded animal, which method comprises: administering to the animal at least one interferon formulated for short-term use; adjusting the dosage with the short-term formulation to increase therapeutic response while simultaneously decreasing adverse side effects; subsequently selecting a dosage to be administered as a long-term formulation showing a controlled rate of release over time; thereafter administering the long-term formulation to release the interferon at a controlled rate over time; and subsequently optionally adjusting the level of interferon released with an additional long-term formulation to further maximize therapeutic response while simultaneously minimizing adverse side effects.
 2. The method of claim 1, wherein the animal is a human.
 3. The method of claim 2, wherein the interferon is selected from natural or recombinant alpha, beta, consensus, gamma, leukocyte, omega, or tau interferon or versions thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding, or mixtures thereof.
 4. The method of claim 3, wherein the interferon-responsive disease is selected from viral hepatitis C, viral hepatitis B, condyloma accuminata, hairy cell leukemia, malignant melanoma, follicular lymphoma, AID's related Kaposi's sarcoma, multiple sclerosis, chronic granulomatous disease, pulmonary fibrosis, and tuberculosis.
 5. The method of claim 3, wherein the interferon-responsive disease is selected from viral hepatitis C, viral hepatitis B, condyloma accuminata, hairy cell leukemia, malignant melanoma, follicular lymphoma, AID's related Kaposi's sarcoma and the interferon is selected from natural or recombinant alpha, consensus, leukocyte, omega or tau interferon or versions thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding, or mixtures thereof.
 6. The method of claim 3, wherein the interferon-responsive disease is selected from chronic granulomatous disease, pulmonary fibrosis, and tuberculosis and the interferon is natural or recombinant gamma interferon or a version thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding.
 7. The method of claim 3, wherein the disease is multiple sclerosis and the interferon is selected from alpha, beta, consensus, leukocyte, omega or tau interferon or versions thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding, or mixtures thereof.
 8. The method of claim 3, wherein the same interferon is administered in the short-term formulation as is administered in the subsequent long-term formulation of interferon.
 9. The method of claim 2, wherein a first interferon is administered as a short-term formulation and a different interferon is subsequently administered in the long-term formulation.
 10. The method of claim 2, wherein the short-term formulation and the long-term formulation are the same.
 11. The method of claim 2, wherein the short-term formulation and the long-term formulation are two different formulations.
 12. The method of claim 2, wherein more than one interferon is administered for short-term use, each interferon being in the same formulation or in different short-term formulations.
 13. The method of claim 2, wherein more than one interferon is administered for long-term use, each interferon being with the same or with different long-term formulation.
 14. The method of claim 2, wherein the short-term formulation is administered first and the long-term formulation is subsequently administered either with or without an overlap of dosing with the short-term and long-term formulations.
 15. The method of claim 2, wherein the controlled release dosage per time unit selected for the long-term formulation is about equivalent to the dosage release over the time unit for the short-term formulation.
 16. The method of claim 2, wherein the controlled release dosage per time unit selected for the long-term formulation is different than that administered with the short-term formulation.
 17. The method of claim 2, wherein the short-term delivery formulation is delivered by an injection, an infusion, an implantable system, a transdermal delivery system, an oral formulation, non-oral parenteral formulation, or an inhalational device.
 18. The method of claim 2, wherein the long-term delivery formulation is an implantable or injectable, non-bioerodible device; an implantable or injectable bioerodible system; a transdermal delivery system; or a chronic intravascular infusion system.
 19. The method of claim 18, wherein the interferon is selected from naturally occurring alpha, beta, consensus, gamma, leukocyte, omega, or tau interferon, or versions thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding, or mixtures thereof.
 20. The method of claim 19, wherein the interferon is omega interferon.
 21. A method for individualizing doses of an interferon in the treatment of interferon-responsive disorders in a warm-blooded animal, which method comprises administering at least one interferon, formulated for short-term use, in a plurality of the animals adjusting the dosage with the short-term formulation to increase therapeutic response while simultaneously decreasing adverse side effects; determining the most commonly identified optimal dosage over time in a sufficiently large population of the animals to define such dosage as a unit dose; subsequently, defining a long-term formulation for delivering such dosage over time as more unit-dose or a fraction thereof, such that, in aggregate, the optimal dosage identified during dosing with the short-term formulation can be approximated with the unit-dose or fractional unit-dose combination using the long-term formulation to deliver the interferon in a controlled dose over time; selecting a dosage to be administered to an individual animal with a long-term delivery; thereafter administering the long-term dosage with a long-term delivery system; and subsequently adjusting, if necessary, the dosage over time with the long-term formulation to further maximize therapeutic response with simultaneously minimizing adverse side effects.
 22. The method of claim 21, wherein the animal is a human.
 23. The method of claim 22, wherein the interferon is selected from natural or recombinant alpha, beta, consensus, gamma, leukocyte, omega, or tau interferon, or versions thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding, or mixtures thereof.
 24. The method of claim 22, wherein the interferon-responsive disease is selected from viral hepatitis C, viral hepatitis B, viral hepatitis D, condyloma accuminata, hairy cell leukemia, malignant melanoma, multiple myeloma, follicular lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, chronic myelogenous leukemia, basal cell carcinoma, mycosis fungoides, carcinoid syndrome, superficial bladder cancer, renal cell cancer, colorectal cancer, laryngeal papillomatosis, actinic keratosis, Kaposi's sarcoma, multiple sclerosis, chronic granulomatous disease, pulmonary fibrosis, and tuberculosis.
 25. The method of claim 22, wherein the interferon-responsive disease is selected from viral hepatitis C, viral hepatitis B, viral hepatitis D, condyloma accuminata, hairy cell leukemia, malignant melanoma, multiple myeloma, follicular lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, chronic myelogenous leukemia, basal cell carcinoma, mycosis fungoides, carcinoid syndrome, superficial bladder cancer, renal cell cancer, colorectal cancer, laryngeal papillomatosis, actinic keratosis, Kaposi's sarcoma, and the interferon is selected from natural or recombinant alpha, consensus, leukocyte, omega or tau interferon or versions thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding, or mixtures thereof.
 26. The method of claim 22, wherein the interferon-responsive disease is selected from chronic granulomatous disease, pulmonary fibrosis, and tuberculosis and the interferon is natural or recombinant gamma interferon or a version thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding.
 27. The method of claim 22, wherein the disease is multiple sclerosis and the interferon is selected from alpha, beta, consensus, leukocyte, omega or tau interferon or versions thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding, or mixtures thereof.
 28. The method of claim 22, wherein the same interferon is administered in the short-term formulation and in the long-term formulation.
 29. The method of claim 22, wherein a first interferon is administered as a short-term formulation and a different interferon is administered as the long-term formulation.
 30. The method of claim 22, wherein the same formulation is administered as the short-term formulation and the subsequent long-term formulation.
 31. The method of claim 22, wherein the short-term formulation differs from the subsequent long-term formulation.
 32. The method of claim 22, wherein more than one interferon is administered for short-term use, each interferon being in the same or in different short-term formulations.
 33. The method of claim 22, wherein more than one interferon is administered for long-term use, each interferon being with the same or with different long-term delivery systems.
 34. The method of claim 22, wherein the short-term formulation is administered first and the long-term formulation is subsequently administered either with or without an overlap of dosing with the short-term and long-term formulations.
 35. The method of claim 22, wherein the controlled release dosage per time unit selected for the long-term formulation is about equivalent to the dosage release over the time unit for the short-term formulation.
 36. The method of claim 22, wherein the controlled release dosage per time unit selected for the long-term formulation is different than that administered with the short-term formulation.
 37. The method of claim 23, wherein the short-term delivery formulation is selected from an injection, an infusion, an implantable system, a transdermal delivery system, an oral formulation, non-oral parenteral administration, or an inhalational device.
 38. The method of claim 37, wherein the interferon is selected from naturally occurring alpha, beta, consensus, gamma, leukocyte, omega, or tau interferon, or versions thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding, or mixtures thereof.
 39. The method of claim 22, wherein the long-term delivery formulation is selected from an implantable, non-erodible device; an implantable or injectable erodible system; a gel or other dispersion; a transdermal delivery system; a chronic intravascular infusion system; an oral formulation; or an inhalational device; and the like.
 40. The method of claim 39, wherein the interferon is selected from naturally occurring alpha, beta, consensus, gamma, leukocyte, omega, or tau interferon, or versions thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding, or mixtures thereof.
 41. A method of manufacturing a long-term delivery device for delivering a drug over time, which method comprises preparing a long-term delivery device designed for delivery of a drug at a relatively constant rate over time, the rate being determined to be a unit rate designed for a patient to receive a standard dosage rate to treat a disease state in the patient treatable over time by the drug, and preparing a long-term delivery device designed for delivery of the same drug at a relatively constant rate over time, which rate is a fraction of the standard dosage rate, wherein each device is suitable for presentation to a patient in need thereof alone or in combination with an identical device or the other device, depending on the dosage rate or fractional dosage rate determined to be appropriate for the patient.
 42. The method of claim 41, wherein the rate of delivery of the drug from the reduced rate device is about fifty percent of the rate of delivery from the standard rate device.
 43. The method of claim 41, which method further comprises preparing dosing instructions for adjusting the rate of administration of the drug by employing one or a combination of devices to achieve the desired release rate of the drug for a patient depending on the patient's needs over time.
 44. The method of claim 41, wherein the drug is an interferon.
 45. The method of claim 44, wherein the interferon is selected from natural or recombinant alpha, beta, consensus interferon, gamma, leukocyte, omega, or tau interferon, or versions thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding, or mixtures thereof.
 46. The method of claim 41, wherein the disease state is an interferon-responsive disease.
 47. The method of claim 46, wherein the interferon-responsive disease is selected from viral hepatitis C, viral hepatitis B, viral hepatitis D, condyloma accuminata, hairy cell leukemia, malignant melanoma, multiple myeloma, follicular lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, chronic myelogenous leukemia, basal cell carcinoma, mycosis fungoides, carcinoid syndrome, superficial bladder cancer, renal cell cancer, colorectal cancer, laryngeal papillomatosis, actinic keratosis, Kaposi's sarcoma, multiple sclerosis, chronic granulomatous disease, pulmonary fibrosis, tuberculosis.
 48. The method of claim 47, wherein the drug is an interferon selected from natural or recombinant alpha, consensus, leukocyte, omega or tau interferon or versions thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding, or mixtures thereof.
 49. The method of claim 48, wherein the disease is hepatitis C and the interferon is omega interferon.
 50. The method of claim 48, wherein the disease is hepatitis C and the interferon is an alpha interferon.
 51. The method of claim 48, wherein the disease is hepatitis C and the interferon is a consensus interferon.
 52. The method of claim 48, wherein the disease is hepatitis C and the interferon is a natural or recombinant interferon.
 53. The method of claim 46, wherein the interferon-responsive disease is selected from chronic granulomatous disease, pulmonary fibrosis, and tuberculosis and the interferon is natural or recombinant gamma interferon or a version thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding.
 54. The method of claim 44, wherein the disease is multiple sclerosis and the interferon is selected from alpha, beta, consensus, leukocyte, omega or tau interferon or versions thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding, or mixtures thereof.
 55. A kit useful for delivery of a relatively constant amount of a drug thereof over time, wherein the amount of drug delivered to an individual patient within a population of patients can be adjusted to the patient's individual needs for treatment, the kit comprising (a) at least one long-term delivery device designed for delivery of a drug at a relatively constant rate over time, the rate being determined to be a unit rate as a standard dosage to treat a disease state in a patient in the population over time, and at least one long-term delivery device designed for delivery of the same drug at a relatively constant rate over time, which rate is a fraction of the standard dosage rate, wherein each device in the kit is suitable for presentation to a patient in need thereof alone or in combination with an identical device or the other device, depending on the dosage rate determined to be appropriate for the patient, or (b) at least two long-term delivery devices designed for delivery of the same drug at the same or different yet relatively constant rates over time, for which each rate is a fraction of the standard dosage rate, wherein each device in the kit is suitable for presentation to a patient in need thereof along or in combination with an identical device or the other device, depending on the dosage rate determined to be appropriate for the patient.
 56. The kit of claim 55, wherein the rate of delivery of the drug from the fractional rate device is about thirty-three percent of the rate of delivery from the standard rate device.
 57. The kit of claim 55, which kit further comprises dosing instructions for adjusting the rate of administration of the drug by employing a combination of devices to achieve the desired release rate of the drug for a patient depending on the patient's needs over time.
 58. The kit of claim 55, wherein the drug is an interferon.
 59. The kit of claim 55, wherein the interferon is selected from the following: natural or recombinant alpha, beta, consensus interferon, gamma, leukocyte, omega, or tau interferon, or versions thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding, or mixtures thereof.
 60. The kit of claim 55, wherein the disease state is an interferon-responsive disease.
 61. The kit of claim 60, wherein the interferon-responsive disease is selected from viral hepatitis C, viral hepatitis B, viral hepatitis D, condyloma accuminata, hairy cell leukemia, malignant melanoma, multiple myeloma, follicular lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, chronic myelogenous leukemia, basal cell carcinoma, mycosis fungoides, carcinoid syndrome, superficial bladder cancer, renal cell cancer, colorectal cancer, laryngeal papillomatosis, actinic keratosis, Kaposi's sarcoma, multiple sclerosis, chronic granulomatous disease, pulmonary fibrosis, tuberculosis.
 62. The kit of claim 61, wherein the drug is an interferon selected from natural or recombinant alpha, consensus, leukocyte, omega or tau interferon or versions thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding, or mixtures thereof.
 63. The kit of claim 61, wherein the disease is hepatitis C and the interferon is omega-interferon.
 64. The kit of claim 60, wherein the interferon-responsive disease is selected from chronic granulomatous disease, pulmonary fibrosis, and tuberculosis and the interferon is natural or recombinant gamma interferon or a version thereof to which polyethylene glycol or a polyethylene glycol—fatty acid moiety has been attached by covalent or non-covalent bonding. 